A non-invasive method that provides quantitative data on the microscopic condition of muscle could revolutionize the management of patients with neuromuscular diseases, ranging from amyotrophic lateral sclerosis to muscular dystrophy. While imaging techniques such as ultrasound and MRI can provide useful and important measures of gross muscle size and the presence of edema or fatty infiltration in the muscle, these modalities provide minimal information on the microscopic condition of the muscle itself. One technological approach that could potentially come close to serving as a virtual muscle biopsy is electrical impedance myography (EIM). Impedance measurements have long been known to provide indirect measures of cell size, extracellular milieu and, with the application of very high frequency current, intracellular structure. The recent development of EIM, a muscle-focused, non-invasive impedance technique, now makes this new objective possible. Obviously, it is unreasonable to expect that a non-invasive technique can achieve all that is possible with actual muscle tissue, such as immunohistochemistry and biochemical analysis. Yet, it may be possible to obtain a wealth of quantitative information about the microscopic condition of muscle in order to assist with initial diagnosis and, more likely, disease monitoring during therapy trial in a wide variety of neuromuscular conditions. The underlying hypothesis of this research is that by applying multifrequency electrical impedance measurements in conjunction with finite element and electrical equivalent circuit analytic techniques, we can obtain quantitative information on certain microscopic features of muscle non-invasively. We plan to test this idea by studying a variety of mouse models. In our first aim, we will focus on the accurate measurement of muscle fiber size by establishing a relationship between impedance parameters and muscle fibers of varying size, including those from immature animals, drug-induced hypertrophy, and a disease model. The second specific aim will focus on the measurement of the extracellular space by assessment of low-frequency data in several models including the mdx mouse, the db/db obese mouse, and a model of drug-induced inflammation. In the third specific aim, we will focus on identifying intracellular abnormalities, including abnormal mitochondrial content, abnormal accumulations of glycogen, and vacuolization. In the fourth aim, we will utilize the developed analytic techniques to evaluate groups of animals to which the researchers are blinded. Finally, as part of our research sharing plans, we will develop an online user interface that will help ensure that the results of this work are widely available to researchers including those with only a passing familiarity with electrical impedance methodologies.

Public Health Relevance

A tool to non-invasively assess the microscopic state of muscle would add greatly to our ability to find new, effective treatments for a variety of neuromuscular conditions, ranging from amyotrophic lateral sclerosis to muscular dystrophy. One approach would be the application of electrical impedance-based methods at a wide range of frequencies in conjunction with advanced analytical techniques. By studying a variety of diseased mouse models, we will develop a non-invasive, painless method for identifying the pathological characteristics of tissue that can be used by clinicians and researchers in the management of a wide range of disorders affecting nerve and muscle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS091159-01A1
Application #
9027963
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2015-09-15
Project End
2020-07-31
Budget Start
2015-09-15
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$349,441
Indirect Cost
$124,803
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Li, Jia; Pacheck, Adam; Sanchez, Benjamin et al. (2016) Single and modeled multifrequency electrical impedance myography parameters and their relationship to force production in the ALS SOD1G93A mouse. Amyotroph Lateral Scler Frontotemporal Degener 17:397-403